title: Interleukin-10-mediated heme oxygenase 1-induced underlying mechanism in inflammatory down-regulation by norfloxacin in cirrhosis.
abstract: Patients with cirrhosis receiving norfloxacin show a restored inflammatory balance that likely prevents clinical complications derived from an excessive proinflammatory response to bacterial product challenges. This study sought to investigate associated inflammatory control mechanisms established in patients with cirrhosis receiving norfloxacin. A total of 62 patients with cirrhosis and ascites in different clinical conditions were considered. Blood samples were collected and intracellular and serum norfloxacin were measured. Inflammatory mediators were evaluated at messenger RNA and protein levels. Neutrophils from all patients were cultured with lipopolysaccharide (LPS) and anti-interleukin-10 (anti-IL-10) monoclonal antibody in different conditions. IL-10 and heme oxygenase-1 (HO-1) were up-regulated in patients receiving norfloxacin and correlated with norfloxacin in a concentration-dependent manner, whereas proinflammatory inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor-κB behaved inversely. Higher IL-10 levels correlated with lower white blood cell count and higher mean arterial pressure. No correlations were found between IL-10 and disease clinical scores or liver function markers in blood. Neutrophilic in vitro assays showed that the effect of LPS on proinflammatory mediator levels in the presence of norfloxacin was abrogated by significantly increasing IL-10 and HO-1 expression. After stimulation with LPS plus anti-IL-10, proinflammatory mediators were dramatically increased in patients receiving norfloxacin, and increasing intracellular norfloxacin concentrations did not decrease the expression levels of these proinflammatory molecules. Unblocking IL-10 restored proinflammatory mediator and HO-1 expression to previously observed levels in response to LPS stimulation.
  
  
  CONCLUSIONS
  Although the described association does not necessarily mean causality, an IL-10-mediated HO-1-induced anti-inflammatory mechanism is present in patients with cirrhosis receiving norfloxacin, that is directly associated with cell-modulating events in these patients.
authors.affiliation: Hepatic Unit and Clinical Pharmacology Service, Hospital General Universitario de Alicante, Universidad Miguel Hernández, Elche, Alicante, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gómez-Hurtado
authors.forename: Pedro
authors.initials: P
authors.lastname: Zapater
authors.forename: Pablo
authors.initials: P
authors.lastname: Bellot
authors.forename: Sonia
authors.initials: S
authors.lastname: Pascual
authors.forename: Miguel
authors.initials: M
authors.lastname: Pérez-Mateo
authors.forename: José
authors.initials: J
authors.lastname: Such
authors.forename: Rubén
authors.initials: R
authors.lastname: Francés
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004269:DNA, Bacterial / Q000097:blood; D015536:Down-Regulation; D005260:Female; D051547:Heme Oxygenase-1 / Q000097:blood / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology / Q000502:physiology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009643:Norfloxacin / Q000097:blood / Q000627:therapeutic use*; D010538:Peritonitis / Q000517:prevention & control; D011446:Prospective Studies; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D004269:DNA, Bacterial; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016753:Interleukin-10; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D009643:Norfloxacin